Resistance to extinction after variable training as a function of multiple associations.
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Animals↗
Biomedical subjects
J B Long
Publications and source records attributed to J B Long.
Three-dimensional distribution of collateral blood flow within the anatomic area at risk after circumflex coronary artery occlusion in dogs.
It is generally accepted that occlusion of a major coronary artery in the dog results in a transmural gradient of collateral blood flow, with the subepicardial region receiving the greatest perfusion. The lateral and base to apex distribution of collateral blood flow and of metabolic and functional consequences of ischemia have been more difficult to define. One reason for such difficulties has been the failure to define the anatomic boundaries of the ischemic vascular bed so that uncontaminated samples of ischemic and non-ischemic tissue could be selected for study. In the present study, the three dimensional distribution of myocardial blood flow during occlusion of the circumflex artery was mapped in seven dogs. At the end of the study, the boundaries of previously ischemic and non-ischemic regions were identified by simultaneous coronary perfusion with red and blue dyes. Left ventricular slices were separated into ischemic and non-ischemic vascular beds based on the dye boundaries, with 1-2 mm of tissue trimmed from this interface to eliminate visually apparent admixture. The ischemic vascular bed of each cross sectional slice then was cut into five transmural wedges, each 3-5 mm wide; each wedge was further subdivided into subendocardial, middle, and subepicardial thirds. The results of blood flow measurements in these samples indicate that the dye injection technique identifies a real interface with a sharp lateral transition in blood flow between ischemic and non-ischemic vascular beds. Within the ischemic vascular bed, there is a transmural gradient of collateral blood flow, but within a given mural layer, there is no consistent gradient from the center to lateral edge or from base to apex of the ischemic region. Thus, in studies designed to characterize the properties of myocardium on either side of the ischemic/non-ischemic interface, reasonable resolution can be achieved by coronary dye infusions to permit visual identification of this interface. On the other hand, in studies in which collateral blood flow is measured as a baseline predictor of infarct size, measurements can be made in a central ischemic block which will be representative of most or all of the ischemic region. Borderzone samples can be excluded to avoid contamination of ischemic samples with non-ischemic tissue.
Animals↗
Cardiovascular effects of dynorphin A (1-13) in conscious rats and its modulation of morphine bradycardia over time.
The short-term cardiovascular effects of dynorphin A (1-13), as well as its effects upon morphine bradycardia were investigated. In unanesthetized, unrestrained rats, intracerebroventricular (ICV) dynorphin A (1-13) injections (10-20 micrograms) produced a dose-related pressor effect, whereas intravenous (IV) dynorphin A (1-13) (1.0 mg/kg) produced a depressor effect; these responses persisted less than five min. Heart rate was not significantly altered by these doses or routes of administration. Dynorphin A (1-13) also produced behavioral effects in the unanesthetized animals, such as wet dog shakes in response to IV administration and wet dog shakes accompanied by barrel rolling in response to ICV administration. To evaluate the effects of dynorphin A (1-13) pretreatment on the bradycardic response to IV morphine, rats were pretreated with 10 micrograms dynorphin A (1-13) ICV four, six or eight hours prior to challenge with morphine sulfate (0.1 mg/kg IV). Four hour pretreatment with dynorphin A (1-13) (tested at 14:00 hr) resulted in a potention of morphine bradycardia, with six hours pretreatment (tested at 16:00 hr) no effect was observed, and eight hours following dynorphin A (1-13) pretreatment (tested at 18:00 hr) morphine bradycardia was attenuated. Additionally, the bradycardic response to IV morphine alone became more exaggerated as rats approached their nocturnal activity cycle. These data further establish that dynorphin A (1-13) exerts a potent, long lasting modulatory effect on morphine bradycardia and emphasize the importance of circadian variables in altering the magnitude of cardiovascular responses to opioid agonists.
Analysis of Variance↗
Hindlimb paralytic effects of arginine vasopressin and related peptides following spinal subarachnoid injection in the rat.
Intrathecal (IT) injection of arginine vasopressin (AVP) in rats caused a transient (less than 30 min), dose-related paralysis of the hindlimbs, loss of hindlimb and tail nociceptive responsiveness, and increased mean arterial pressure. Motor dysfunction was produced with comparable potency by lysine vasopressin (LVP) and arginine vasotocin (AVT); oxytocin (OXY) was approximately 1000 times less potent. Paralysis induced by these peptides was selectively blocked following IT pretreatment with 0.5 nmoles of the vasopressin V1 receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine] Arg8-vasopressin (d(CH2)5[Tyr(Me2)]AVP). Pressor and antinociceptive responses to AVP were also blocked by this compound. However, at higher doses (2-5 nmoles, IT), d(CH2)5[Tyr(Me2)]AVP produced hindlimb paralysis, antinociception, and pressor responses by itself. In contrast to the fiber degeneration, cell loss, and necrosis found in lumbosacral cords of rats persistently paralyzed by other peptides (dynorphin A, somatostatin, and ICI 174864), neuropathological changes were not evident in spinal cords of rats transiently paralyzed by IT AVP. These results indicate that AVP-related peptides affected diverse spinal cord functions through interactions with a V1-like receptor. The similar pattern of cardiovascular and antinociceptive responses to other peptides (dynorphin A, somatostatin, and ICI 174864), which also caused hindlimb paralysis, suggests that the former responses may actually reflect the nonselective consequences of a peptide-induced disruption of spinal cord function, rather than specific shared pharmacological effects.
Animals↗
Upregulation of the opioid receptor complex by the chronic administration of morphine: a biochemical marker related to the development of tolerance and dependence.
Studies conducted after the development of the rapid filtration assay for opiate receptors, and before the recognition of multiple opioid receptors, failed to detect changes in opioid receptors induced by chronic morphine. Recent experiments conducted in our laboratories were designed to examine the hypothesis that only one of several opioid receptor types might be altered by chronic morphine. Using binding surface analysis and irreversible ligands to increase the "resolving power" of the ligand binding assay, the results indicated that chronic morphine increased both the Bmax and Kd of the opioid receptor complex, labeled with either [3H][D-Ala2,D-Leu5]enkephalin, [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin or [3H]6-desoxy-6 beta-fluoronaltreone. In the present study rats were pretreated with drugs known to attenuate the development of tolerance and dependence [the irreversible mu-receptor antagonist, beta-funaltrexamine (beta-FNA), and the inhibitor of tryptophan hydroxylase, para-chlorophenylalanine], prior to subcutaneous implantation of morphine pellets. The results demonstrated that 1) unlike chronic naltrexone, beta-FNA failed to upregulate opioid receptors and 2) both beta-funaltrexamine and PCPA pretreatment attenuated the chronic morphine-induced increase in the Bmax, but not the Kd, of the opioid receptor complex. These results provide evidence that naltrex-one-induced upregulation of the opioid receptor complex might occur indirectly as a consequence of interactions at beta-funaltrexamine-insensitive opioid receptors and that morphine-induced upregulation (increased Bmax) of the opioid receptor complex is a relevant in vitro marker related to the development of tolerance and dependence. These data collectively support the hypothesis that endogenous antiopiate peptides play an important role in the development of tolerance and dependence to morphine.
Amino Acid Sequence↗
Chronic intracerebroventricular infusion of the antiopioid peptide, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (NPFF), downregulates mu opioid binding sites in rat brain.
Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (NPFF), an endogenous mammalian antiopioid peptide, has been shown by other laboratories to attenuate the acute antinociceptive effects of morphine, the development of morphine tolerance, and naloxone-induced withdrawal in morphine-dependent rats. The present study determined the effect of chronic NPFF on mu opioid receptors and mRNA for the endogenous opioids dynorphin and enkephalin. Rats received ICV infusions of either saline or NPFF (5 micrograms/h) for 13 days via Alzet 2002 osmotic minipumps. Homogenate binding studies, which used whole brain membranes, demonstrated that NPFF decreased the Bmax of mu binding sites (labeled by [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin) from 262 +/- 12 to 192 +/- 12 fmolmg protein, and increased the Kd from 1.1 to 2.3 nM. Quantitative receptor autoradiography and in situ hybridization experiments were conducted with sections collected at the level of the striatum. The density of mu opioid binding sites labeled by [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin was decreased in all brain areas measured except the corpus callosum, and there was no change in dynorphin mRNA or enkephalin mRNA in the caudate, the nucleus accumbens, or the ventral pallidum. Rats chronically administered ICV morphine sulfate (20 micrograms/h) for 14 days developed tolerance to morphine and a low degree of dependence, as measured by naloxone-precipitated withdrawal. Chronic administration of NPFF concurrently with morphine sulfate did not significantly alter naloxone-induced withdrawal signs or the development of morphine tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗